Why did we fund this project?

'This is a good study looking at the cause of Alzheimer's disease, and as such is key to a better understanding of the disease.'

'Improved understanding of all relevant processes in Alzheimer's disease is of the utmost importance.'

What do we already know?

Memory is made possible by the ability of synapses, the connections between nerve cells (neurones) in the brain, to change in response to environmental inputs. In Alzheimer's disease, memory declines because synapses and neurones become dysfunctional and die. In fact, loss of synapses is a strong predictor of dementia in people with Alzheimer's disease.

Several degenerative processes are known to occur in the brains of people withAlzheimer's disease. The amyloid-beta protein clumps into plaques, which accumulate all over the brain, and tau protein forms into neurofibrillary tangles, which start in the areas of the brain important for memory then march throughout the rest of the brain assymptoms progress. In this project, the researchers will ask whether tau causes synapse death and look for the reasons that synapses die.

One factor leading from tau to synapse loss may be problems with moving mitochondria to synapses. Mitochondria are the 'batteries' of all cells, using oxygen and sugar to make energy. The proper distribution of mitochondria throughout the cell is essential to maintaining cellular health. In neurones, this is a particularly important because these brain cells have high energy demands.

The long branches of neurones that carry signals from one part of the brain to another or from the brain all the way to the bottom of the spinal cord present unique challenges to cellular transport. Tau is normally bound to structures that form the skeleton of the cells, called microtubules, which form the 'tracks' for this transport throughout the cell, and during Alzheimer's the tracks become disrupted as tau detaches and forms into tangles. Previous work has shown that the transport of mitochondria in neurones is disrupted by tau in Alzheimer's models. What is not known is how this affects synapses.

This project is an important step in understanding why dementia occurs and how to treat it.

What does this project involve?

To answer these questions, the researchers will use both models of Alzheimer's disease and donated human brain tissue. The brain tissue will have markers applied to it to identify synapses and mitochondria and high-resolution microscope work will be used to create images of these. From these images, the researchers will learn whether synapses are lost when tau is present and whether transport of mitochondria to synapses is impaired.

This method of looking at synapses is new and was developed for use in human brain tissue by Dr Spires-Jones. In fact, these researchers have the only brain 'bank' of donated brain samples prepared for this technique. One important side benefit of this project is banking and sharing these precious donated samples with other researchers to answer many questions about why the brain degenerates in Alzheimer's disease.

How will this benefit people with dementia?

Finding out why synapses die during Alzheimer's disease is an essential step towards developing treatments for the disease. In this project, the researchers will test one treatment in disease models (reducing tau protein) to determine whether this can save synapses. If so, this treatment may help people with dementia in the future.